Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance and progressive pancreatic ?-cell dysfunction. While insulin resistance often initiates the disease, it is the failure of ?-cells to compensate that drives hyperglycemia and disease progression. Preserving or restoring ?-cell function is thus a critical goal in T2DM management. This review outlines the underlying mechanisms of ?-cell dysfunction, including glucotoxicity, lipotoxicity, oxidative stress, and inflammation. It also explores current and emerging strategies to overcome ?-cell failure, such as lifestyle interventions, pharmacological agents, incretin-based therapies, islet regeneration, and novel cellular approaches. Targeting ?-cell dysfunction offers the potential to halt or even reverse T2DM, paving the way for personalized and durable therapeutic strategies.
